A number of aromatic diamidines have been shown to bind to the minor-groove of DNA, and to exhibit useful antimicrobial activity. Various hypotheses of the mode of antimicrobial action of the aryl amidines have been proposed, however evidence is growing that these compounds function by complex formation with DNA and subsequent selective inhibition of DNA dependent microbial enzymes. Intervention in transcription control has been demonstrated and seems to be a plausible mode of action for structurally diverse minor groove binders. (Das, B. P.; Boykin, D. W., J. Med. Chem. 1977, 20, 531-536; Boykin, D. W. et al., J. Med. Chem. 1995, 36, 912-916; Kumar, A. et al., Eur. J. Med. Chem. 1996, 31, 767-773; Lombardy, R. J. et al., J. Med. Chem. 1996,31, 912-916; Tidwell, R. R. et al., Antimicrob. Agents Chemother. 1993, 37, 1713-1716; Tidwell, R. R.; Bell, C. A., Pentamidine and Related Compounds in Treatment of Pneumocystis carinii Infection, in Pneumocystis carinii, Ed Marcel Decker; New York, 1993, 561-583; Henderson, D.; Hurley, L. H., Nature Med. 1995, 1, 525-527; Mote, J. Jr., et al., J. Mol. Biol. 1994, 226, 725-737; Boykin, D. W., et al., J. Med. Chem. 1998, 41, 124-129).
The antimicrobial and nucleic acid binding properties of amidino- and cyclic-amidino-2,5-diarylf urans have been demonstrated. See, e.g., U.S. Pat. No. 5,602,172. The bis(phenylamidinium) compounds have established activity against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model. PCP affects a high proportion of patients with suppressed immunsystems such as people with AIDS, and it is a major cause of mortality in these individuals. X-ray crystallographic, molecular modeling and other biophysical studies have demonstrated that these compounds strongly bind to DNA by H-bonding between the furan group and the floor of the minor groove, and by non-bonded interactions to the walls of the AT-rich minor groove.